Common Deletions

The polymorphic marker D7S1870, which lies within the proximal part of GTF2I, was initially shown to be deleted in every patient with a diagnosis of classic WBS. D7S489B, however, which lies near Frizzled 9 (FZD9), was shown to be present in all such patients (6,47,48,50,51). Subsequently, it has been shown that in approx 95% of WBS patients, the deletion occurs between highly homologous sequences within the centromeric and medial B-blocks, whereas in the remainder it occurs between sequences in the adjacent A-blocks (Fig. 3) (31). These two block pairs are the only ones that are directly oriented with respect to each other (Fig. 1). The predominance of recombination between the B-blocks, rather than the A-blocks is postulated to occur because of the higher sequence identity (99.6 vs 98.2%), more contiguous homology (there are two interstitial deletions of the medial A-block), and the shorter distance between the blocks (1.55 vs 1.84 Mb). In addition, the active transcription of all three of the GTF2I genes within the testes and in blastocysts suggests that they are transcribed in germ cells, which could induce an open chromatic formation that is conducive to recombination (6,52).

The exceptionally high identity between repeat-block sequences copies has made it extremely difficult to identify the exact deletion breakpoints in patients. Site-specific nucleotide differences (SSNs) between the repeats, also referred to as paralagous sequence variants or c/s-morphisms, have been utilized to study the relative copy number of different segments of the B-block, allowing the sites of recombination to be mapped (31). These elegant studies have revealed a 1.4-kb recombination hotspot within GTF2I, which accounts for one-third of all deletions arising on a noninverted chromosome (53). Other breakpoints exist throughout the remainder of GTF2I, NCF1, and GTF2IRD2, with additional hot spots associated with both paternally inherited and maternally inherited deletions (53). This translates into a variable number of genes within the deletion; 26 if the recombination occurs in GTF2I, up to 28 if it

Fig. 4. Genotype-phenotype correlation in Williams-Beuren syndrome (WBS). The WBS region is shown including all the known genes and the flanking repeats depicted as shaded boxes. Seventeen patients with smaller deletions of the region are listed beneath (with references) and the extent of their deletions are represented as lines between non-deleted blocks (unknown breakpoints lie within the white areas). They are shown in groups of increasing phenotypic complexity, with patients showing the classic WBS phenotype at the bottom of the page. The proposed WBS minimal critical region is indicated with brackets.

Fig. 4. Genotype-phenotype correlation in Williams-Beuren syndrome (WBS). The WBS region is shown including all the known genes and the flanking repeats depicted as shaded boxes. Seventeen patients with smaller deletions of the region are listed beneath (with references) and the extent of their deletions are represented as lines between non-deleted blocks (unknown breakpoints lie within the white areas). They are shown in groups of increasing phenotypic complexity, with patients showing the classic WBS phenotype at the bottom of the page. The proposed WBS minimal critical region is indicated with brackets.

occurs within GTF2IRD2 or the A-block. The inclusion of NCF1 within the deletion is supported by two reports of patients with WBS and chronic granulomatous disease (OMIM no. 233700), presumably owing to a mutation of the intact NCF1 gene (54,55). A recent correlation has been made between the deletion of NCF1 and reduced incidence of hypertension in WBS (56). It has also been suggested that hypertension is linked to parent-of-origin (57), however, this may reflect the predominance of paternally inherited deletions that have recombination breakpoints within the GTF2I hotspot, thereby leaving NCF1 intact (53).

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